rs3752752

Positions:

• chr10-71695444-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022124.6(CDH23):​c.2316T>C​(p.Asn772Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.678 in 1,611,520 control chromosomes in the GnomAD database, including 375,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30289 hom., cov: 34)
  • Exomes 𝑓: 0.68 (344852 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.08

Genes affected

CDH23 (HGNC:13733): (cadherin related 23) This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 10-71695444-T-C is Benign according to our data. Variant chr10-71695444-T-C is described in ClinVar as [Benign]. Clinvar id is 45893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71695444-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.2316T>C	p.Asn772Asn	synonymous_variant	22/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.2316T>C	p.Asn772Asn	synonymous_variant	22/32		NP_001165401.1
CDH23	NM_001171931.2	c.2316T>C	p.Asn772Asn	synonymous_variant	22/26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.2316T>C	p.Asn772Asn	synonymous_variant	22/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.625 AC: 95005 AN: 151954 Hom.: 30281 Cov.: 34

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.654

GnomAD3 exomes AF: 0.628 AC: 156598 AN: 249186 Hom.: 50665 AF XY: 0.641 AC XY: 86665 AN XY: 135198

Gnomad AFR exome AF: 0.521

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.765

Gnomad EAS exome AF: 0.503

Gnomad SAS exome AF: 0.631

Gnomad FIN exome AF: 0.558

Gnomad NFE exome AF: 0.712

Gnomad OTH exome AF: 0.656

GnomAD4 exome AF: 0.683 AC: 997094 AN: 1459448 Hom.: 344852 Cov.: 42 AF XY: 0.684 AC XY: 496665 AN XY: 726120

Gnomad4 AFR exome AF: 0.512

Gnomad4 AMR exome AF: 0.475

Gnomad4 ASJ exome AF: 0.771

Gnomad4 EAS exome AF: 0.483

Gnomad4 SAS exome AF: 0.634

Gnomad4 FIN exome AF: 0.566

Gnomad4 NFE exome AF: 0.712

Gnomad4 OTH exome AF: 0.670

GnomAD4 genome AF: 0.625 AC: 95044 AN: 152072 Hom.: 30289 Cov.: 34 AF XY: 0.617 AC XY: 45890 AN XY: 74328

Gnomad4 AFR AF: 0.528

Gnomad4 AMR AF: 0.564

Gnomad4 ASJ AF: 0.781

Gnomad4 EAS AF: 0.478

Gnomad4 SAS AF: 0.618

Gnomad4 FIN AF: 0.554

Gnomad4 NFE AF: 0.711

Gnomad4 OTH AF: 0.650

Alfa AF: 0.700 Hom.: 59492

Bravo AF: 0.623

Asia WGS AF: 0.523 AC: 1819 AN: 3478

EpiCase AF: 0.727

EpiControl AF: 0.731

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2012	Caucasian frequency = 4989/6832 (ESP data) -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 1D Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.16
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3752752; hg19: chr10-73455201; COSMIC: COSV54935616;